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1.
Eur Respir Rev ; 33(172)2024 Apr.
Article in English | MEDLINE | ID: mdl-39009409

ABSTRACT

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.


Subject(s)
Idiopathic Pulmonary Fibrosis , Phosphoric Diester Hydrolases , Receptors, Lysophosphatidic Acid , Signal Transduction , Humans , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Receptors, Lysophosphatidic Acid/metabolism , Animals , Signal Transduction/drug effects , Phosphoric Diester Hydrolases/metabolism , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Molecular Targeted Therapy , Lung/drug effects , Lung/physiopathology , Lung/metabolism , Antifibrotic Agents/therapeutic use , Lysophospholipids/metabolism , Treatment Outcome , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/physiopathology , Phosphodiesterase Inhibitors/therapeutic use
2.
OMICS ; 28(7): 367-376, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38986084

ABSTRACT

Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.


Subject(s)
Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Signal Transduction , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Humans , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Signal Transduction/drug effects , Lysophospholipids/metabolism , Gene Expression Profiling/methods , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Female , Sphingosine/analogs & derivatives
3.
Cells ; 13(13)2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38995003

ABSTRACT

Lung parenchymal hypoxia has emerged as a cardinal feature of idiopathic pulmonary fibrosis (IPF). Hypoxia promotes cancer cell invasion and metastasis through signaling that is dependent upon the lysophosphatidic acid (LPA) receptor, LPA1 (LPAR1). Abundant data indicate that LPA1-dependent signaling also enhances lung fibrogenesis in IPF. We recently reported that fibroblasts isolated from the lungs of individuals with IPF have an increased capacity to form subcellular matrix-degradative structures known as invadosomes, an event that correlates with the degree of lung fibrosis. We therefore hypothesized that hypoxia promotes invadosome formation in lung fibroblasts through LPA1-dependent signaling. Here, it is demonstrated that invadosome formation by fibroblasts from the lungs of individuals with advanced IPF is inhibited by both the tyrosine receptor kinase inhibitor nintedanib and inhibition of LPA1. In addition, exposure of normal human lung fibroblasts to either hypoxia or LPA increased their ability to form invadosomes. Mechanistically, the hypoxia-induced invadosome formation by lung fibroblasts was found to involve LPA1 and PDGFR-Akt signaling. We concluded that hypoxia increases the formation of invadosomes in lung fibroblasts through the LPA1 and PDGFR-Akt signaling axis, which represents a potential target for suppressing lung fibrosis.


Subject(s)
Fibroblasts , Lung , Podosomes , Receptors, Lysophosphatidic Acid , Signal Transduction , Humans , Fibroblasts/metabolism , Fibroblasts/pathology , Lung/pathology , Lung/metabolism , Podosomes/metabolism , Receptors, Lysophosphatidic Acid/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/metabolism , Cell Hypoxia , Lysophospholipids/metabolism , Indoles/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism
4.
Int J Mol Sci ; 25(13)2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38999980

ABSTRACT

We have previously reported that, in aortic rings, 18:1 lysophosphatidic acid (LPA) can induce both vasodilation and vasoconstriction depending on the integrity of the endothelium. The predominant molecular species generated in blood serum are poly-unsaturated LPA species, yet the vascular effects of these species are largely unexplored. We aimed to compare the vasoactive effects of seven naturally occurring LPA species in order to elucidate their potential pathophysiological role in vasculopathies. Vascular tone was measured using myography, and thromboxane A2 (TXA2) release was detected by ELISA in C57Bl/6 mouse aortas. The Ca2+-responses to LPA-stimulated primary isolated endothelial cells were measured by Fluo-4 AM imaging. Our results indicate that saturated molecular species of LPA elicit no significant effect on the vascular tone of the aorta. In contrast, all 18 unsaturated carbon-containing (C18) LPAs (18:1, 18:2, 18:3) were effective, with 18:1 LPA being the most potent. However, following inhibition of cyclooxygenase (COX), these LPAs induced similar vasorelaxation, primarily indicating that the vasoconstrictor potency differed among these species. Indeed, C18 LPA evoked a similar Ca2+-signal in endothelial cells, whereas in endothelium-denuded aortas, the constrictor activity increased with the level of unsaturation, correlating with TXA2 release in intact aortas. COX inhibition abolished TXA2 release, and the C18 LPA induced vasoconstriction. In conclusion, polyunsaturated LPA have markedly increased TXA2-releasing and vasoconstrictor capacity, implying potential pathophysiological consequences in vasculopathies.


Subject(s)
Aorta , Lysophospholipids , Mice, Inbred C57BL , Thromboxane A2 , Vasoconstriction , Animals , Thromboxane A2/metabolism , Vasoconstriction/drug effects , Mice , Lysophospholipids/metabolism , Lysophospholipids/pharmacology , Aorta/drug effects , Aorta/metabolism , Male , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Vasodilation/drug effects , Calcium/metabolism
5.
Int J Mol Sci ; 25(13)2024 Jul 06.
Article in English | MEDLINE | ID: mdl-39000547

ABSTRACT

Mood disorders affect over 300 million individuals worldwide, often characterized by their chronic and refractory nature, posing significant threats to patient life. There has been a notable increase in mood disorders among American adolescents and young adults, with a rising number of suicide attempts and fatalities, highlighting a growing association between mood disorders and suicidal outcomes. Dysregulation within the neuroimmune-endocrine system is now recognized as one of the fundamental biological mechanisms underlying mood and mood disorders. Lysophosphatidic acid (LPA), a novel mediator of mood behavior, induces anxiety-like and depression-like phenotypes through its receptors LPA1 and LPA5, regulating synaptic neurotransmission and plasticity. Consequently, LPA has garnered substantial interest in the study of mood regulation. This study aimed to elucidate the molecular mechanisms of lysophosphatidic acid and its receptors, along with LPA receptor ligands, in mood regulation and to explore their potential therapeutic efficacy in treating mood disorders. A comprehensive literature search was conducted using the PubMed and Web of Science databases, identifying 208 articles through keyword searches up to June 2024. After excluding duplicates, irrelevant publications, and those restricted by open access limitations, 21 scientific papers were included in this review. The findings indicate that LPA/LPA receptor modulation could be beneficial in treating mood disorders, suggesting that pharmacological agents or gintonin, an extract from ginseng, may serve as effective therapeutic strategies. This study opens new avenues for future research into how lysophosphatidic acid and its receptors, as well as lysophosphatidic acid receptor ligands, influence emotional behavior in animals and humans.


Subject(s)
Lysophospholipids , Mood Disorders , Receptors, Lysophosphatidic Acid , Humans , Lysophospholipids/metabolism , Receptors, Lysophosphatidic Acid/metabolism , Animals , Mood Disorders/metabolism , Mood Disorders/drug therapy , Affect , Signal Transduction , Plant Extracts
6.
Sci Rep ; 14(1): 15444, 2024 07 04.
Article in English | MEDLINE | ID: mdl-38965272

ABSTRACT

Tobacco smoking is the main etiological factor of lung cancer (LC), which can also cause metabolome disruption. This study aimed to investigate whether the observed metabolic shift in LC patients was also associated with their smoking status. Untargeted metabolomics profiling was applied for the initial screening of changes in serum metabolic profile between LC and chronic obstructive pulmonary disease (COPD) patients, selected as a non-cancer group. Differences in metabolite profiles between current and former smokers were also tested. Then, targeted metabolomics methods were applied to verify and validate the proposed LC biomarkers. For untargeted metabolomics, a single extraction-dual separation workflow was applied. The samples were analyzed using a liquid chromatograph-high resolution quadrupole time-of-flight mass spectrometer. Next, the selected metabolites were quantified using liquid chromatography-triple-quadrupole mass spectrometry. The acquired data confirmed that patients' stratification based on smoking status impacted the discriminating ability of the identified LC marker candidates. Analyzing a validation set of samples enabled us to determine if the putative LC markers were truly robust. It demonstrated significant differences in the case of four metabolites: allantoin, glutamic acid, succinic acid, and sphingosine-1-phosphate. Our research showed that studying the influence of strong environmental factors, such as tobacco smoking, should be considered in cancer marker research since it reduces the risk of false positives and improves understanding of the metabolite shifts in cancer patients.


Subject(s)
Biomarkers, Tumor , Lung Neoplasms , Metabolomics , Smoking , Humans , Lung Neoplasms/blood , Lung Neoplasms/metabolism , Metabolomics/methods , Biomarkers, Tumor/blood , Male , Female , Middle Aged , Smoking/blood , Smoking/adverse effects , Aged , Sphingosine/analogs & derivatives , Sphingosine/blood , Sphingosine/metabolism , Lysophospholipids/blood , Lysophospholipids/metabolism , Metabolome , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/blood , Chromatography, Liquid/methods , Succinic Acid/blood , Succinic Acid/metabolism , Glutamic Acid/blood , Glutamic Acid/metabolism
7.
Int J Mol Sci ; 25(14)2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39062979

ABSTRACT

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.


Subject(s)
Lysophospholipids , Neoplasms , Phosphoric Diester Hydrolases , Humans , Phosphoric Diester Hydrolases/metabolism , Phosphoric Diester Hydrolases/genetics , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Lysophospholipids/metabolism , Animals , Signal Transduction , Receptors, Lysophosphatidic Acid/metabolism , Receptors, Lysophosphatidic Acid/genetics , Carcinogenesis/genetics , Carcinogenesis/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism
8.
Neurobiol Dis ; 199: 106585, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38955289

ABSTRACT

Sphingosine-1 phosphate (S1P) is a lipid metabolite regulating diverse biological processes, including proliferation, differentiation, migration, and apoptosis, highlighting its physiological and therapeutic significance. Current S1P-based therapeutic approaches primarily focus on modulating the downstream signalling via targeting S1P receptors, however, this is challenged by incomplete receptor internalisation. Sphingosine-1-phosphate lyase (SPL) is a highly conserved enzyme that "gatekeeps" the final step of S1P degradation. Cognisant of the complex ligand and receptor interaction and dynamic metabolic networks, the selective modulation of SPL activity presents a new opportunity to regulate S1P biosynthesis and reveal its role in various systems. Over the past decade, an evolving effort has been made to identify new molecules that could block SPL activity in vitro or in vivo. This review focuses on summarising the current understanding of the reported SPL inhibitors identified through various screening approaches, discussing their efficacy in diverse model systems and the possible mechanism of action. Whilst effective modulation of S1P levels via inhibiting SPL is feasible, the specificity of those inhibitors remains inconclusive, presenting a clear challenge for future implications. Yet, none of the currently available SPL inhibitors is proven effective in elevating S1P levels within the central nervous system. This review article embraces future research focusing on investigating selective SPL inhibitors with high potency and possibly blood-brain-barrier permeability, which would aid the development of new S1P-based therapeutics for neurological disorders.


Subject(s)
Aldehyde-Lyases , Lysophospholipids , Sphingosine , Aldehyde-Lyases/metabolism , Aldehyde-Lyases/antagonists & inhibitors , Humans , Animals , Lysophospholipids/metabolism , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use
9.
J Gene Med ; 26(6): e3708, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38837511

ABSTRACT

BACKGROUND: Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA1-LPA6). Our previous study demonstrated that the LPA-producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain. METHODS: MTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA-stimulated esophageal epithelial cells (Het-1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early-stage ESCC. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA-mediated communication between epithelial cells and cancer cells. RESULTS: Functional experiments showed that exposing ESCC cancer cells to CM from LPA-treated Het-1a results in promoting proliferation, migration, invasion and epithelial-mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro-migration influence of CM derived from LPA-treated Het-1a. Mechanism studies have demonstrated that LPA activated the NF-κB signaling pathway through LPA1/3, ultimately causing an increase in CCL2 expression and secretion in Het-1a. CONCLUSIONS: Our findings, taken together, demonstrate that CM from LPA-treated esophageal epithelial cells plays a significant role in promoting the progression of ESCC, with CCL2 acting as the primary regulator.


Subject(s)
Cell Movement , Cell Proliferation , Chemokine CCL2 , Epithelial Cells , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Gene Expression Regulation, Neoplastic , Lysophospholipids , Humans , Lysophospholipids/metabolism , Lysophospholipids/pharmacology , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/genetics , Chemokine CCL2/metabolism , Chemokine CCL2/genetics , Epithelial Cells/metabolism , Epithelial Cells/drug effects , Cell Proliferation/drug effects , Cell Line, Tumor , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Cell Movement/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Disease Progression , Signal Transduction/drug effects , Esophagus/metabolism , Esophagus/pathology , Esophagus/drug effects , Epithelial-Mesenchymal Transition/drug effects
10.
Biomolecules ; 14(6)2024 May 28.
Article in English | MEDLINE | ID: mdl-38927035

ABSTRACT

Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma. The LPA effects and the participation of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) in LPA mitogenic signaling were studied in human neuroblastoma cell lines. We used light microscopy and [3H]-thymidine incorporation to determine cell proliferation, Western blot to study intracellular signaling, and pharmacological and molecular tools to examine the role of ALK. We found that LPA stimulated the growth of human neuroblastoma cells, as indicated by the enhanced cell number, clonogenic activity, and DNA synthesis. These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. In a panel of human neuroblastoma cell lines harboring different ALK genomic status, the ALK inhibitors suppressed LPA-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), which are major regulators of cell proliferation. ALK depletion by siRNA treatment attenuated LPA-induced ERK1/2 activation. LPA enhanced ALK phosphorylation and potentiated ALK activation by the ALK ligand FAM150B. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK.


Subject(s)
Anaplastic Lymphoma Kinase , Cell Proliferation , Lysophospholipids , Neuroblastoma , Signal Transduction , Humans , Lysophospholipids/metabolism , Lysophospholipids/pharmacology , Anaplastic Lymphoma Kinase/metabolism , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Neuroblastoma/metabolism , Neuroblastoma/pathology , Cell Proliferation/drug effects , Cell Line, Tumor , Signal Transduction/drug effects , Phosphorylation/drug effects , Piperidines/pharmacology , Carbazoles/pharmacology , Forkhead Box Protein O3/metabolism , Forkhead Box Protein O3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase 3/genetics , MAP Kinase Signaling System/drug effects
11.
Int J Mol Sci ; 25(12)2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38928268

ABSTRACT

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-ß) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-ß and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-ß1 (ß1), 1 µM sphingosine-1-phosphate (S1P), and 5 µM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) ß1/S1P; (3) ß1/I2; prevention groups; (4) S1P/ß1; and (5) I2/ß1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-ß signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-ß binding proteins (LTBPs), TGF-ß receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-ß receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.


Subject(s)
Cornea , Fibrosis , Lysophospholipids , Signal Transduction , Sphingosine , Transforming Growth Factor beta , Humans , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Sphingosine/pharmacology , Lysophospholipids/metabolism , Lysophospholipids/pharmacology , Cornea/metabolism , Cornea/pathology , Cornea/drug effects , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Fibroblasts/metabolism , Fibroblasts/drug effects , Cells, Cultured , Sphingolipids/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Corneal Diseases/metabolism , Corneal Diseases/pathology , Corneal Diseases/drug therapy
12.
Sci Rep ; 14(1): 13655, 2024 06 13.
Article in English | MEDLINE | ID: mdl-38871974

ABSTRACT

Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (TazKD) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of TazKD mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in TazKD mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.


Subject(s)
Acyltransferases , Barth Syndrome , Cardiolipins , Disease Models, Animal , Mitochondria, Heart , Mitophagy , Animals , Barth Syndrome/metabolism , Barth Syndrome/genetics , Barth Syndrome/pathology , Barth Syndrome/drug therapy , Mitophagy/drug effects , Mice , Acyltransferases/metabolism , Acyltransferases/genetics , Cardiolipins/metabolism , Mitochondria, Heart/metabolism , Mitochondria, Heart/drug effects , Transcription Factors/metabolism , Transcription Factors/genetics , Lysophospholipids/metabolism , Mice, Knockout , Oligopeptides
13.
JCI Insight ; 9(11)2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38855867

ABSTRACT

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.


Subject(s)
ADAM10 Protein , Antigens, CD , Arthritis, Experimental , Arthritis, Rheumatoid , Cadherins , Endothelial Cells , Sphingosine-1-Phosphate Receptors , Animals , Cadherins/metabolism , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine-1-Phosphate Receptors/genetics , Mice , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Antigens, CD/metabolism , Antigens, CD/genetics , Endothelial Cells/metabolism , Humans , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Arthritis, Rheumatoid/genetics , ADAM10 Protein/metabolism , ADAM10 Protein/genetics , Amyloid Precursor Protein Secretases/metabolism , Signal Transduction , Mice, Knockout , Membrane Proteins/metabolism , Membrane Proteins/genetics , Male , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Lysophospholipids/metabolism , Capillary Permeability , Female
14.
Lipids Health Dis ; 23(1): 200, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38937745

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI. METHODS: Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann-Whitney test) and by Tukey's correction for multiple comparisons. RESULTS: In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days. CONCLUSIONS: Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.


Subject(s)
Brain , Ceramides , Sphingolipids , Sphingomyelin Phosphodiesterase , Sphingosine , Animals , Mice , Sphingolipids/blood , Sphingolipids/metabolism , Brain/metabolism , Brain/pathology , Ceramides/blood , Ceramides/metabolism , Sphingomyelin Phosphodiesterase/metabolism , Sphingomyelin Phosphodiesterase/blood , Sphingomyelin Phosphodiesterase/genetics , Sphingosine/analogs & derivatives , Sphingosine/blood , Sphingosine/metabolism , Disease Models, Animal , Male , Sphingomyelins/blood , Sphingomyelins/metabolism , Brain Concussion/blood , Brain Concussion/metabolism , Mice, Inbred C57BL , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/blood , Brain Injuries, Traumatic/pathology , Lysophospholipids/blood , Lysophospholipids/metabolism
15.
J Bioenerg Biomembr ; 56(4): 475-482, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38886303

ABSTRACT

Lysophosphatidic acid (LPA) is a simple lipid which is endogenously synthesized from lysophosphatidylcholine (LPC) by autotaxin (ATX). LPA mediates a variety of cellular responses through the binding of G protein-coupled LPA receptors (LPA1 to LPA6). It is considered that LPA receptor-mediated signaling plays an important role in the pathogenesis of human malignancy. Genetic alterations and epigenetic changes of LPA receptors have been detected in some cancer cells as well as LPA per se. Moreover, LPA receptors contribute to the promotion of tumor progression, including cell proliferation, invasion, metastasis, tumorigenicity, and angiogenesis. In recent studies, the activation of LPA receptor-mediated signaling regulates chemoresistance and radiosensitivity in cancer cells. This review provides an updated overview on the roles of LPA receptor-mediated signaling in the regulation of cancer cell functions and its potential utility as a molecular target for novel therapies in clinical cancer approaches.


Subject(s)
Neoplasms , Receptors, Lysophosphatidic Acid , Signal Transduction , Humans , Receptors, Lysophosphatidic Acid/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Lysophospholipids/metabolism , Animals
16.
Int J Mol Sci ; 25(12)2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38928196

ABSTRACT

LPA3 receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA3-mediated calcium signaling, the agonists, and the phorbol ester-induced LPA3 internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid ß-arrestin-LPA3 receptor association. The agonist and the phorbol ester-induced marked LPA3 receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute ß-arrestin binding sites. These data provide insight into LPA3 receptor signaling and regulation.


Subject(s)
Lysophospholipids , Receptors, Lysophosphatidic Acid , Signal Transduction , Humans , beta-Arrestins/metabolism , Binding Sites , Calcium Signaling , HEK293 Cells , Lysophospholipids/metabolism , Phosphorylation , Receptors, Lysophosphatidic Acid/metabolism
17.
Mol Metab ; 86: 101971, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38925249

ABSTRACT

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Phosphotransferases (Alcohol Group Acceptor) , Sex Characteristics , Animals , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Phosphotransferases (Alcohol Group Acceptor)/genetics , Male , Female , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Mice , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Humans , Mice, Inbred C57BL , Diet, High-Fat/adverse effects , Mice, Knockout , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Lysophospholipids/metabolism , Cell Proliferation
18.
J Lipid Res ; 65(7): 100574, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38857781

ABSTRACT

Bis(monoacylglycerol)phosphate (BMP) is an acidic glycerophospholipid localized to late endosomes and lysosomes. However, the metabolism of BMP is poorly understood. Because many drugs that cause phospholipidosis inhibit lysosomal phospholipase A2 (LPLA2, PLA2G15, LYPLA3) activity, we investigated whether this enzyme has a role in BMPcatabolism. The incubation of recombinant human LPLA2 (hLPLA2) and liposomes containing the naturally occurring BMP (sn-(2-oleoyl-3-hydroxy)-glycerol-1-phospho-sn-1'-(2'-oleoyl-3'-hydroxy)-glycerol (S,S-(2,2',C18:1)-BMP) resulted in the deacylation of this BMP isomer. The deacylation rate was 70 times lower than that of dioleoyl phosphatidylglycerol (DOPG), an isomer and precursor of BMP. The release rates of oleic acid from DOPG and four BMP stereoisomers by LPLA2 differed. The rank order of the rates of hydrolysis were DOPG>S,S-(3,3',C18:1)-BMP>R,S-(3,1',C18:1)-BMP>R,R-(1,1',C18:1)>S,S-(2,2')-BMP. The cationic amphiphilic drug amiodarone (AMD) inhibited the deacylation of DOPG and BMP isomers by hLPLA2 in a concentration-dependent manner. Under these experimental conditions, the IC50s of amiodarone-induced inhibition of the four BMP isomers and DOPG were less than 20 µM and approximately 30 µM, respectively. BMP accumulation was observed in AMD-treated RAW 264.7 cells. The accumulated BMP was significantly reduced by exogenous treatment of cells with active recombinant hLPLA2 but not with diisopropylfluorophosphate-inactivated recombinant hLPLA2. Finally, a series of cationic amphiphilic drugs known to cause phospholipidosis were screened for inhibition of LPLA2 activity as measured by either the transacylation or fatty acid hydrolysis of BMP or phosphatidylcholine as substrates. Fifteen compounds demonstrated significant inhibition with IC50s ranging from 6.8 to 63.3 µM. These results indicate that LPLA2 degrades BMP isomers with different substrate specificities under acidic conditions and may be the key enzyme associated with BMP accumulation in drug-induced phospholipidosis.


Subject(s)
Lysophospholipids , Lysosomes , Monoglycerides , Humans , Lysosomes/metabolism , Lysosomes/enzymology , Monoglycerides/metabolism , Lysophospholipids/metabolism , Animals , Mice , Phospholipases A2/metabolism , Phospholipids/metabolism , Liposomes/metabolism , Lipidoses/metabolism , Lipidoses/chemically induced , Lipidoses/enzymology
19.
Exp Neurol ; 379: 114864, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38866101

ABSTRACT

Platelet-derived growth factor receptor ß positive (PDGFRß+) pericytes detach from the microvascular wall and migrate into the injury center following spinal cord injury (SCI), which has been widely regarded as the main source of fibrotic scar, but the mechanism of migration and fibroblast transition remains elusive. Here we show the associated spatiotemporal distribution between microglia and pericytes at three and seven days post-injury (dpi). The increased expression of Sphingosine kinase-1 (SPHK1) in microglia significantly raised the concentration of Sphingosine-1-phosphate (S1P) in the spinal cord, which promotes migration and fibroblast transition of pericyte. In vitro experiments, we found the elevated Sphingosine 1-phosphate receptor 3 (S1P3), the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted its nuclear translocation, which contributed to the formation of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1) protein, This process can be blocked by an S1P3 specific inhibitor TY52156 in vitro. The S1P/S1P3/YAP pathway might be a potential target for treatment in SCI.


Subject(s)
Cell Movement , Fibroblasts , Lysophospholipids , Microglia , Pericytes , Signal Transduction , Sphingosine-1-Phosphate Receptors , Sphingosine , Spinal Cord Injuries , YAP-Signaling Proteins , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology , Signal Transduction/physiology , Lysophospholipids/metabolism , Animals , Cell Movement/physiology , Pericytes/metabolism , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Microglia/metabolism , YAP-Signaling Proteins/metabolism , Rats , Fibroblasts/metabolism , Sphingosine-1-Phosphate Receptors/metabolism , Rats, Sprague-Dawley , Adaptor Proteins, Signal Transducing/metabolism , Receptors, Lysosphingolipid/metabolism , Cells, Cultured
20.
Lipids Health Dis ; 23(1): 204, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38943207

ABSTRACT

Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.


Subject(s)
Bone Neoplasms , Lysophospholipids , Receptors, Lysophosphatidic Acid , Signal Transduction , Humans , Lysophospholipids/metabolism , Bone Neoplasms/secondary , Bone Neoplasms/metabolism , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Signal Transduction/drug effects , Receptors, Lysophosphatidic Acid/metabolism , Receptors, Lysophosphatidic Acid/genetics , Animals
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